Beta2 adrenoceptor genotype and preterm labor

Beta2 肾上腺素受体基因型与早产

• 批准号: 7101100
• 负责人: RICHARD M SMILEY
• 金额: $ 31.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101100
• 关键词: beta adrenergic receptor; clinical research; epidemiology; female; gene environment interaction; genetic polymorphism; genetic susceptibility; human pregnant subject; human therapy evaluation; muscle contraction; myometrium; pharmacogenetics; pregnancy disorder chemotherapy; premature labor; racial /ethnic difference; receptor sensitivity; terbutaline; tocolytic agents

DESCRIPTION (provided by applicant): Preterm birth is a major public health problem in the United States, occurring in approximately 11% of pregnancies, and contributing to 70-85% of perinatal morbidity and mortality. Individual, racial, and ethnic differences in incidence at outcome from preterm labor (PTL) are likely based, at least in part, on genetic differences between populations. The beta2-adrenergic receptor has long been a therapeutic target in the treatment of (PTL) since Beta2AR stimulation promotes uterine relaxation. The therapeutic response to and side-effect profile of drugs differs significantly between individuals and groups due to genetic variation in drug metabolism and the structure or function of the therapeutic target. Single nucleotide polymorphisms (genetic variations) of the Beta2AR have been described which differ in function and response to stimulation with agonists. Our preliminary data demonstrate that the Arg 16 genotype of the Beta2AR is associated with protection from preterm delivery and a significantly better response to Beta2-agonist tocolysis when preterm labor occurs. The arginine genotype is associated with decreased desensitization of the receptor in response to stimulation, suggesting that this form of the receptor might better maintain uterine quiescence in the face of environmental conditions (e.g., infection, inflammation, multiple gestation) which can predispose to preterm labor. It is the goal of this project to define the role of genetic variability in the B2AR in the incidence of preterm labor in a prospective, treatment-standardized cohort study, in women from several ethnic groups, and to define the role of B2AR genotype in the response to tocolytic b-adrenoceptor agonist treatment. Women from three different ethnic groups (Caucasian, African-American, and Hispanic) will be studied. The B2AR genotype distribution in women with preterm labor will be compared to women delivering at term within each ethnic population to determine the effect of Beta2AR genotype on the incidence of preterm labor. Women with preterm labor will be treated with a protocol including the B2AR agonist terbutaline and the effect of Beta2AR genotype on the success, failure, and side effects of treatment will be defined. Our findings will contribute to understanding of the individual genetic factors and ethnic/racial epidemiology contributing to preterm delivery and will help to target appropriate therapy to defined populations on the basis of modern genetic knowledge.

描述(申请人提供)：在美国，早产是一个主要的公共卫生问题，发生在大约11%的怀孕中，占围产儿发病率和死亡率的70%-85%。早产(PTL)结局发生率的个体、种族和民族差异可能至少部分地基于人群之间的遗传差异。长期以来，β2-肾上腺素能受体一直是治疗甲状旁腺功能减退症(PTL)的靶点，因为β2受体刺激促进子宫松弛。由于药物代谢和治疗靶点的结构或功能的遗传差异，药物的治疗反应和副作用在个体和群体之间存在显著差异。已经描述了Beta2AR的单核苷酸多态(遗传变异)，其功能和对激动剂刺激的反应不同。我们的初步数据表明，当早产发生时，Beta2AR的Arg16基因型与早产的保护和对Beta2激动剂宫缩的显著反应有关。精氨酸基因型与受体对刺激反应的脱敏程度降低有关，这表明这种形式的受体在面临可能导致早产的环境条件(例如感染、炎症、多胎)时可能更好地保持子宫静止。本项目的目标是在一项前瞻性的标准化治疗队列研究中，确定B2AR基因变异在早产发生率中的作用，并确定B2AR基因在溶胎b肾上腺素能受体激动剂治疗反应中的作用。来自三个不同种族(高加索人、非裔美国人和西班牙裔)的女性将被研究。对早产妇女和足月分娩妇女在各民族人群中的B2AR基因分布进行比较，以确定β2AR基因对早产发生率的影响。早产妇女将接受包括B2AR激动剂特布他林的治疗方案，并将确定Beta2AR基因对治疗成功、失败和副作用的影响。我们的发现将有助于了解导致早产的个体遗传因素和民族/种族流行病学，并将有助于根据现代遗传知识针对特定人群进行适当的治疗。